The studies proposed in this grant are designed to provide new understanding of the role of both indoor allergen exposure and IgE antibodies specific for these proteins in relation to the prevalence and severity of asthma. Our recent investigation of a novel form of anaphylaxis identified IgE antibodies specific for the oligosaccharide galactose--1,3-galactose (alpha-gal) that are induced by tick bites. Those responses are common in the southeastern United States and are associated with delayed anaphylaxis following 3-4 hours after consumption of red meat. In keeping with that, the experiments proposed here take advantage of the fact that there are two allergens (alpha-gal and peanut) where sensitization appears to have become more common and which i) give rise to high titer IgE antibodies, ii) are thought to induce IgE antibodies by going through the skin, and iii) are not associated with asthma. Our central hypothesis is that IgE antibodies to protein antigens are an important contributor to asthma if they are chronically inhaled, and also that higher titers of these IgE antibodies increase that risk. The proposed experiments address several aspects of the problem from: I. Studies in developing or pre-hygiene regions, designed to understand why children in those countries do not have either high titer IgE antibodies to inhalant allergens or allergic asthma. These studies will include a comparison of home environments, allergic sensitization, clinical symptoms, and stool microbiome in Ecuador, Costa Rica, and Virginia. II. Studies within a Western post-hygiene environment focused on the evidence that different routes of exposure influence IgE antibody responses. These studies will investigate the effects of allergens on the skin in inducing Th2-related responses, with or without disruption of the skin barrier. The studies will also address the question whether changes in the skin due to excessive cleaning of infants could have contributed to the increase in IgE antibodies. III. We will use two different approaches to investigate the relevance of high titer IgE antibodies to understanding acute exacerbations of asthma. Those studies will first study children presenting with acute exacerbations to the hospital emergency room, and second, carry out RV challenges on adult subjects with asthma, using a new RV-16 pool. These studies will focus on the mechanisms by which Rhinovirus acts to cause exacerbation of allergic asthma. Taken together, the experiments proposed here have the potential to: i) explain the effects of high titer on prevalence and severity of asthma, ii) identify targets for treatment designed to reduce the severity of disease and the risk of exacerbations, and iii) provide information about why allergic diseases are continuing to increase in prevalence.